Investigation of base excision repair gene variants in late-onset Alzheimer's disease

Author(s)

Ertuzun, Tugce ^{[1, 2]} ; Semerci, Asli ^[2] ; Cakir, Mehmet Emin ^[3] ; Ekmekcioglu, Aysegul ^[2] ; Gok, Mehmet Oguz ^{[2, 4]} ; Soltys, Daniela T. ^[5] ; de Souza-Pinto, Nadja C. ^[5] ; Sezerman, Ugur ^[6] ; Muftuoglu, Meltem ^{[1, 2]}

Affiliation

^[1] Acibadem Mehmet Ali Aydinlar Univ, Dept Mol Biol & Genet, Istanbul - Turkey

^[2] Acibadem Mehmet Ali Aydinlar Univ, Dept Med Biotechnol, Istanbul - Turkey

^[3] Medeniyet Univ, Goztepe Training & Res Hosp, Dept Neurol, Istanbul - Turkey

^[4] Univ Texas Southwestern Med Ctr Dallas, Div Basic Sci, Dallas, TX 75390 - USA

^[5] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil

^[6] Acibadem Mehmet Ali Aydinlar Univ, Dept Biostat & Med Informat, Istanbul - Turkey

• Document type: Journal article
• Source: PLoS One; v. 14, n. 8 AUG 15 2019.
• Web of Science Citations: 0

Abstract

Base excision repair (BER) defects and concomitant oxidative DNA damage accumulation play a role in the etiology and progression of late-onset Alzheimer's disease (LOAD). However, it is not known whether genetic variant(s) of specific BER genes contribute to reduced BER activity in LOAD patients and whether they are associated with risk, development and/or progression of LOAD. Therefore, we performed targeted next generation sequencing for three BER genes, uracil glycosylase (UNG), endonuclease VIII-like DNA glycosylase 1 (NEIL1) and polymerase beta (POL beta) including promoter, exonic and intronic regions in peripheral blood samples and postmortem brain tissues (temporal cortex, TC and cerebellum, CE) from LOAD patients, high-pathology control and cognitively normal age-matched controls. In addition, the known LOAD risk factor, APOE was included in this study to test whether any BER gene variants associate with APOE variants, particularly APOE epsilon 4. We show that UNG carry five significant variants (rs1610925, rs2268406, rs80001089, rs1018782 and rs1018783) in blood samples of Turkish LOAD patients compared to age-matched controls and one of them (UNG rs80001089) is also significant in TC from Brazilian LOAD patients (p<0.05). The significant variants present only in CE and TC from LOAD are UNG rs2569987 and POL beta rs1012381950, respectively. There is also significant epistatic relationship (p = 0.0410) between UNG rs80001089 and NEIL1 rs7182283 in TC from LOAD subjects. Our results suggest that significant BER gene variants may be associated with the risk of LOAD in non-APOE epsilon 4 carriers. On the other hand, there are no significant UNG, NEIL1 and POL beta variants that could affect their protein level and function, suggesting that there may be other factors such as post-transcriptional or-translational modifications responsible for the reduced activities and protein levels of these genes in LOAD pathogenesis. Further studies with increased sample size are needed to confirm the relationship between BER variants and LOAD risk. (AU)

• FAPESP's process: 17/04372-0 - Mitochondrial DNA: mechanisms for genome integrity maintenance and impact on disease
• Grantee: Nadja Cristhina de Souza Pinto
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/51906-1 - Mitochondrial bioenergetics, ion transport, redox state and DNA metabolism
• Grantee: Alicia Juliana Kowaltowski
• Support Opportunities: Research Projects - Thematic Grants